This multi-disciplinary and multi-institutional application aims to provide the answer to a key question in human health and nutrition: how do poorly bioavailable dietary polyphenols from fruits and vegetables lower the risk of chronic diseases, such as metabolic syndrome (MetS) and type-2 diabetes (T2D), associated with low-grade chronic inflammation. Using a high fat diet (HFD)-induced metabolic syndrome (MetS) and type-2 diabetes (T2D) murine model coupled with metagenomics and transcriptomics, we will investigate the hypothesis that poorly bioavailable dietary polyphenols from fruits and vegetables act directly in the gastrointestinal (GI) tract to remodel the gut microbiota and reduce local and systemic inflammation via interdependent mechanisms resulting in a reduction in chronic disease risk. While epidemiological, clinical and preclinical studies suggest that consumption of polyphenol-rich foods is associated with reduced risk of MetS and T2D, the mechanism(s) of protection offered by polyphenols has remained elusive due to generally poor polyphenol absorption and distribution to target tissues. Recent studies have shown that consumption of a HFD perturbs gut microbiota ecology and promotes intestinal inflammation, which precedes the development of obesity and insulin resistance characteristic of MetS/T2D. Studies in germ- free (GF; i.e. gnotobiotic) or antibiotic-treated mice demonstrated that consumption of HFD in the absence of gut microbiota protected mice from developing the clinical features of MetS/T2D, implicating the gut microbiota as a key player in the etiology of metabolic diseases. The proposed studies aim to show that poorly bioavailable polyphenols provide resilience to MetS/T2D by changing gut microbiota ecology thus reducing inflammation in the intestine. In collaboration with the laboratory of Dr. Peter Turnbaugh, a leading gut microbiota expert at Harvard University we will: 1) Use the HFD-fed C57BL/6J model of MetS/T2D to test the effects of purified polyphenol fractions from grape and cranberry on microbiome ecology, intestinal inflammation, gut barrier integrity, oral glucose tolerance and adiposity; 2) Study the dose response of polyphenols on gut microbiota and oral glucose tolerance in MetS/T2D mice and test the direct effects of polyphenols on microbiota ecology and physiology in vitro and; 3) Use antibiotic- treated MetS/T2D mice, depleted of their gut microbiota, to test direct polyphenol effects on intestinal inflammation and glucose tolerance in the absence of the gut microbiota. The proposed experiments will evaluate the host physiological and nutrigenomic responses to dietary polyphenols and relate these responses to the changes in host microbiota to provide an integrated mechanistic explanation for the health benefits of polyphenol-rich diets. Successful completion of proposed studies may substantiate the old wisdom that an apple a day keeps the doctor away.